Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
The United States and other countries around the world are experiencing a demographic sea change owing to the rapidly growing elderly and ‘Baby Boomer’ populations (Trojanowski, (2008) Neurosignals 16: 5-10). Our astonishing biomedical advances in the last half-century have greatly increased our life expectancy. But as a consequence of living longer, our population now faces an up tick in the incidence of neurodegenerative diseases. These truly disastrous disorders include Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis (ALS) and the frontal temporal dementias (Forman et al. (2004) Nat. Med. 10:1055-1063). Interestingly, though disparate in their pathophysiology, many of these diseases share a common molecular theme manifesting in the accumulation of insoluble protein aggregates in the brain and nervous system. Deciphering the mechanisms causing these proteins to misfold and aggregate and identifying the genes and cellular pathways affected by misfolded human disease proteins will aid the development of new therapeutic approaches, which we are in dire need of.
The protein TDP-43 was recently identified as the major disease protein in pathological inclusions in both ALS and frontal temporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) (Neumann et al. (2006) Science 314: 130-133). Moreover, mutations in the TDP-43 gene have now been identified in sporadic and familial ALS patients (Gitcho et al., (2008) Ann Neurol. 63:535-8; Kabashi et al., (2008) Nat Genet. 40: 572-574; Sreedharan et al., (2008) Science 319: 1668-1672; Van Deerlin et al., (2008) Lancet Neurol. 7: 409-416); Yokoseki et al., (2008) Ann Neurol. 63: 538-542. Pathology and genetics both converge on TDP-43 as being central to the pathogenesis of these diseases. The study of tau, α-synuclein, and amyloid beta in neurodegenerative disorders has revolutionized our understanding of their respective disease mechanisms. A similar intense effort to understand TDP-43 biology and its role in pathology will be beneficial to the development of therapies to treat proteinopathies such as ALS and FTLD-U.